O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth

Nat Commun. 2015 Sep 24;6:8468. doi: 10.1038/ncomms9468.

Abstract

The pentose phosphate pathway (PPP) plays a critical role in macromolecule biosynthesis and maintaining cellular redox homoeostasis in rapidly proliferating cells. Upregulation of the PPP has been shown in several types of cancer. However, how the PPP is regulated to confer a selective growth advantage on cancer cells is not well understood. Here we show that glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP, is dynamically modified with an O-linked β-N-acetylglucosamine sugar in response to hypoxia. Glycosylation activates G6PD activity and increases glucose flux through the PPP, thereby providing precursors for nucleotide and lipid biosynthesis, and reducing equivalents for antioxidant defense. Blocking glycosylation of G6PD reduces cancer cell proliferation in vitro and impairs tumor growth in vivo. Importantly, G6PD glycosylation is increased in human lung cancers. Our findings reveal a mechanistic understanding of how O-glycosylation directly regulates the PPP to confer a selective growth advantage to tumours.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylglucosamine / metabolism*
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Glucose / metabolism*
  • Glucosephosphate Dehydrogenase / metabolism*
  • Glycosylation
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Hypoxia / metabolism*
  • In Vitro Techniques
  • Lung Neoplasms / metabolism*
  • MCF-7 Cells
  • Mice
  • N-Acetylglucosaminyltransferases / metabolism*
  • Neoplasm Transplantation
  • Pentose Phosphate Pathway*
  • Reactive Oxygen Species / metabolism*
  • Up-Regulation

Substances

  • Reactive Oxygen Species
  • Glucosephosphate Dehydrogenase
  • N-Acetylglucosaminyltransferases
  • O-GlcNAc transferase
  • Glucose
  • Acetylglucosamine